JP2018507218A - Composition for prevention, amelioration, or treatment of metabolic diseases containing amodiaquine as an active ingredient - Google Patents

Abstract

The present invention relates to a novel use of a composition comprising an amodiaquine compound or a pharmaceutically acceptable salt thereof as an active ingredient, specifically, an amodiaquine compound or a pharmaceutically acceptable salt thereof. Activating both PPAR-γ (Peroxisome proliferator-activated receptor-gamma) and PPAR-α (Peroxisome proliferator-activated receptor-alpha) of the composition containing as an active ingredient, For improvement or therapeutic use.

Description

  The present invention relates to an amodiakin-containing metabolic disease that activates both PPAR-γ (Peroxisome proliferator-activated receptor-gamma) and PPAR-α (Peroxisome proliferator-activated receptor-alpha) as a prophylactic metabolite of amodiakin. , Improvement or therapeutic compositions.

  The Korean dietary culture is gradually becoming westernized, and metabolic diseases are increasing. One typical metabolic disease is diabetes. Diabetes is because glucose, a glucose-regulating hormone secreted by the pancreatic beta cells, does not produce the amount required by the body or does not act correctly on the cells, so glucose in the blood Is a condition that is not used as, accumulates in blood, induces hyperglycemia, and sugar is detected in urine. In general, diabetes is divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes) depending on whether insulin is essential for treatment. Is done. Type 2 diabetes is non-insulin-dependent diabetes, which is caused by insufficient insulin action due to insulin resistance or relatively insufficient insulin, and 90% of all diabetic patients belong to type 2 diabetes. It is also called adult type diabetes because it mainly develops after the thirties.

  When diabetes is sustained for a long time, glucose absorption in the body does not occur normally, leading to abnormalities in carbohydrate metabolism, lipid metabolism, and protein metabolism, resulting in hyperinsulinemia, neurological complications, diabetic retinopathy (non- Proliferative retinopathy, proliferative retinopathy, diabetic cataract), renal failure, sexual dysfunction, skin disease (allergy), hypertension, arteriosclerosis, stroke (medium wind), heart disease (myocardial infarction, angina) , Heart paralysis), various diabetic complications such as gangrene. Therefore, in order to understand the various causes and pathogenesis of type 2 diabetes and to establish an improvement bill, research on glucose transport and metabolic processes, insulin signal transduction system, etc. has been actively conducted domestically and abroad. The current situation is that no drugs that can be fundamentally treated have been developed.

  Currently known type 2 diabetes mellitus treatment agents can be roughly classified into four types, but they are sulfonylureas drugs that induce insulin secretion, transfer sugar to muscle cells, and suppress sugar synthesis in the liver. Biguanides that show effects, alpha-glucosidase inhibitors that inhibit the enzymes that make glucose in the small intestine, and PPAR (Peroxisome proliferator-activated receptors) -γ that are involved in adipocyte differentiation There are thiazolidinedione (TZD) chemicals. However, such oral hypoglycemic drugs are hypoglycemic (sulfonylurea), nephrotoxic (biguanide), lactic acidosis (biguanide), diarrhea and food (alpha-glucosidase inhibitor) With many side effects.

  Peroxisome is one of the organelles that cause such abnormal metabolic functions, and plays an important role in the metabolism of oxygen, glucose, lipids, and hormones. It also affects the regulation of differentiation and the regulation of inflammatory mediators. Peroxisomes not only affect insulin sensitivity through lipid and glucose metabolism, but also affect the formation of cell membranes and mast cells, affect oxidative stress, and play important roles in aging and tumor development. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate gene expression through ligand binding, and various fatty acids act as endogenous ligands. . Currently revealed PPARs are peroxisome proliferator-activated receptor alpha (PPAR-α), peroxisome proliferator-activated receptor beta / delta (PPAR-β / δ), and peroxisome proliferator-activated receptor. There is a body gamma (PPAR-γ).

  PPAR-γ is most commonly found in adipose tissue, and is also found in vascular endothelium, macrophages, and pancreatic β cells, which regulate adipocyte differentiation and play a crucial role in systemic lipid homeostasis. To do. PPAR-γ fully or partially activating compounds are particularly effective in the treatment of type 2 diabetes. However, obesity, dyslipidemia, cardiovascular disease, fatty liver, etc. that occur as side effects when PPAR-γ is activated are problematic.

  PPAR-α is mainly found in blood vessel walls, liver, heart, muscle, kidney, brown adipose tissue, etc., and together with the action of fibrates, it prevents arteriosclerosis and delays the onset of Has anti-obesity action by promoting oxidization.

  Therefore, a need has been raised for the discovery of new compounds that can more effectively modulate the activity of PPAR for the prevention, amelioration, or treatment of various diseases that are regulated by the action of PPAR.

  Thus, the present inventors have studied on a compound that has excellent anti-diabetic activity and can be safely applied, and has paid attention to amodiaquine.

  Amodiaquine is an antimalarial compound, and many studies on therapeutic agents for malaria have been reported. In addition, the conventional patent-registered technology for amodiaquine shows that an antimalarial preparation for oral administration and a method for producing the same (Korea Patent Registration No. 10-0623322), piperazine derivatives (Korea Patent Registration No. 10- No. 1143785).

  However, there are no studies and techniques for amodiaquine for the prevention, amelioration, or treatment of metabolic diseases as diseases that are regulated by the action of PPAR.

  The present invention relates to a new use of a composition containing amodiaquine or a pharmaceutically acceptable salt thereof as an active ingredient, specifically, PPAR-γ (Peroxisome proliferator-activated receptor-gamma) and PPAR- It is an object of the present invention to provide a novel use for the prevention, amelioration, or treatment of metabolic diseases mediated by α (Peroxisome proliferator-activated receptor-alpha) signal.

  However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the following description.

  The present invention contains an amodiaquin represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and PPAR-γ (Peroxisome proliferator-activated receptor-gamma) and PPAR-α ( Provided is a pharmaceutical composition for preventing or treating metabolic diseases, characterized by activating both peroxisome proliferator-activated receptor-alpha).

  The daily dosage of the composition may be 8 mg / kg to 20 mg / kg.

  The metabolic diseases include diabetes, hyperglycemia, impaired glucose tolerance, obesity, dyslipidemia, arteriosclerosis, hypertension, insulin resistance syndrome, and fat resistance syndrome. It may be one or more selected from the group consisting of liver, cardiovascular disease, and syndrome X.

  The dyslipidemia may be one or more selected from the group consisting of hyperlipidemia, hypertriglyceremia, and hypercholesteremia.

  The metabolic disease may be type 2 diabetes that responds to PPAR-γ activation.

  The metabolic disease is one selected from the group consisting of obesity, dyslipidemia, cardiovascular disease, and fatty liver that occurs as a side effect when PPAR-γ is activated in response to PPAR-α activation That can be the case.

  As one embodiment of the present invention, it contains amodiaquin represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and PAR-γ (Peroxisome proliferator-activated receptor-gamma) and A health functional food composition for preventing or ameliorating metabolic diseases, characterized by activating both PPAR-α (Peroxisome proliferator-activated receptor-alpha).

  The metabolic diseases include diabetes, hyperglycemia, impaired glucose tolerance, obesity, dyslipidemia, arteriosclerosis, hypertension, insulin resistance syndrome, and fat resistance syndrome. It may be one or more selected from the group consisting of liver, cardiovascular disease, and syndrome X.

  The dyslipidemia may be one or more selected from the group consisting of hyperlipidemia, hypertriglyceremia, and hypercholesteremia.

  The metabolic disease may be type 2 diabetes that responds to PPAR-γ activation.

  The metabolic disease is one selected from the group consisting of obesity, dyslipidemia, cardiovascular disease, and fatty liver that occurs as a side effect when PPAR-γ is activated in response to PPAR-α activation That can be the case.

  A composition comprising amodiaquine or a pharmaceutically acceptable salt thereof as an active ingredient according to the present invention comprises PPAR-α (Peroxisome proliferator-activated receptor-alpha) and PPAR-γ (Peroxisome proliferator-activator-activator-activator-activator-activator-activator-activator-activator-activator-activator-activator-activated ) Was promoted. In particular, the composition of the present invention has an effect of increasing glucose absorption value, an effect of enhancing blood glucose and controlling blood glucose, an effect of reducing glycated hemoglobin (HbA1C), an effect of reducing body weight, an effect of heat production, an effect of preventing fatty liver and an anti-inflammatory effect in adipose tissue. Things are diseases related to PPAR diabetes (especially type 2 diabetes), hyperglycemia, glucose intolerance, obesity, dyslipidemia, arteriosclerosis, hypertension, insulin resistance syndrome, fatty liver, cardiovascular system It is expected that it can be conveniently used for prevention, amelioration, or treatment of diseases and metabolic diseases such as syndrome X.

FIG. 1A is a graph showing the effect of amodiaquin on the activation of PPAR-γ (Peroxisome proliferator-activated receptor-gamma). FIG. 1b is a graph showing the effect of amodiaquin on the activation of PPAR-γ (Peroxisome proliferator-activated receptor-gamma). FIG. 1c is a graph showing the effect of activation of PPAR-α (Peroxisome proliferator-activated receptor-alpha). FIG. 1d is a graph showing the effect of activation of PPAR-α (Peroxisome proliferator-activated receptor-alpha). FIG. 2 is a graph obtained by measuring the absorption value of a glucose analog when amodiaquine was treated for 24 hours in a C2C12 myotube cell line, which is a rat-derived muscle cell. FIG. 3a is a graph confirming the effect of amodiaquin intake on fasting blood glucose concentration in mice. FIG. 3b is a graph showing the results of a glucose tolerance test (IPGTT) in which the effect of amodiaquin intake on the change in blood glucose over time after glucose administration to mice was confirmed. FIG. 4 is a graph confirming the effect of amodiaquin intake on glycated hemoglobin levels in mice. FIG. 5a is a graph showing the obesity-inhibiting phenomenon of mice when high fat diet-induced obesity mice are administered with amodiaquine simultaneously with high fat intake. FIG. 5b is a graph showing the average daily feed intake of mice. FIG. 5c is a graph showing the obesity treatment phenomenon by administration of amodiaquine to obese mice (High fat diet-induced obesity mice) induced for a long time (20 weeks) with a high fat diet. FIG. 5d is a graph confirming the daily average feed intake of each mouse. FIG. 6 is a graph showing heat production of high fat diet-induced obese mice when exposed to low temperatures due to ingestion of amodiaquine. FIG. 7a is a graph showing the results of a glucose tolerance test (OGTT) in which the effect of the mice on which the administration of amodiaquine progressed simultaneously with the high fat diet and the change in blood glucose over time after glucose administration was confirmed. FIG. 7 b is a graph showing an insulin tolerance test (IPITT) in which changes in blood glucose concentration over time were confirmed in mice subjected to amodiaquine administration simultaneously with a high fat diet after insulin injection. FIG. 7c is a graph showing an insulin tolerance test (IPITT) in which amodiaquine was administered to a mouse induced for a long time (20 weeks) on a high-fat diet, then insulin was injected, and changes in blood glucose concentration over time were confirmed. is there. FIG. 8 is a graph in which livers were stained with Hematoxylin-Eosin in experimental animals bred for 14 weeks on a high-fat diet with amodiaquine, and histological changes in hepatocytes due to fat accumulation were confirmed. FIG. 9a is a graph showing the results of measuring the expression of genes associated with fatty acid oxidation in hepatocytes of high fat diet-induced obese mice ingesting amodiaquine. FIG. 9b is a graph showing the results of measuring the expression of genes associated with fatty acid oxidation in muscle tissue. FIG. 9c is a graph showing the results of measuring the expression of genes related to fatty acid oxidation in adipose tissue, respectively. FIG. 10 is a graph showing the results of measuring the expression of genes related to anti-inflammatory in the adipose tissue of high fat diet-induced obese mice ingesting amodiaquine.

  The present inventors contain amodiaquine or a pharmaceutically acceptable salt thereof as an active ingredient, and PPAR-γ (Peroxisome proliferator-activated receptor-gamma) and PPAR-α (Peroxisome proliferator-activator-activator-activator-activator-activator-activator-activator-activator-activator-activator-activator-activators The present invention has been completed by developing a composition for the prevention, amelioration or treatment of metabolic diseases characterized by activating both of (alpha).

  In one embodiment of the present invention, the activity of PPAR-γ and PPAR-α was measured using a vector in order to examine whether amodiaquin acts as a dual ligand for PPAR-γ and PPAR-α (Examples). 1), in order to confirm whether the glucose absorption ability of amodiaquine increased and had a blood glucose inhibitory effect, an experiment for evaluating the glucose absorption ability was carried out using a mouse muscle cell line (see Example 2). In addition, hypoglycemic and blood glucose control effects, glycated blood pigment (HbA1C) reduction effect, weight loss effect, heat production effect and fatty liver prevention effect by amodiaquine were investigated in mice (see Examples 3 to 8). It was also confirmed that administration of amodiaquine can regulate the expression of target genes (ACOX, CPT-1 and mCAD) by activation of PPAR-α in liver, muscle and adipose tissue, and promote fatty acid degradation (Examples) 9), it was confirmed that amodiaquine administration can suppress the expression of target genes (TNFα, MCP-1 and iNOS) due to anti-inflammatory reaction in adipose tissue (see Example 10).

  As a result, it was confirmed that activation of PPAR-γ and PPAR-α by amodiaquine treatment and a series of reactions thereby suppress fat accumulation and are effective for blood glucose regulation.

  Therefore, the present invention relates to amodiaquine (4-[(7-chloroquinolin-4-yl) amino] -2-[(diethylamino) methyl] phenol) represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: The salt can be used as a pharmaceutical composition for preventing or treating metabolic diseases, characterized by activating both PPAR-γ and PPAR-α.

  The metabolic diseases include diabetes, hyperglycemia, impaired glucose tolerance, obesity, dyslipidemia, arteriosclerosis, hypertension, insulin resistance syndrome, and fat resistance syndrome. It is characterized by being one or more selected from the group consisting of liver, cardiovascular disease, and syndrome X, but is not limited thereto.

  Further, the dyslipidemia is one or more selected from the group consisting of hyperlipidemia, hypertriglyceremia, and hypercholesterolemia, wherein the hyperlipidemia is hyperlipidemia, hypertriglyceremia, and hypercholesterolemia. However, it is not limited to this.

  At this time, the disease that responds to the activation of PPAR-γ can be type 2 diabetes, and the disease that reacts to the activation of PPAR-α and occurs as a side effect upon the activation of PPAR-γ is obesity. It may be one or more selected from the group consisting of dyslipidemia, cardiovascular disease and fatty liver, but is not limited thereto.

  Therefore, the composition is characterized in that it activates both PPAR-γ and PPAR-α, and can be used for preventive or therapeutic use against type 2 diabetes in response to PPAR-γ activation, In this case, in response to the activation of PPAR-α, one or more selected from the group consisting of obesity, dyslipidemia, cardiovascular disease and fatty liver occurring as a side effect upon activation of PPAR-γ is suppressed. it can.

  The term “treatment” as used in the present invention means all acts in which a symptom for a metabolic disease is improved or advantageously altered by administration of a pharmaceutical composition according to the present invention.

Thus, it can further comprise suitable carriers, excipients, and diluents commonly used for manufacturing as a pharmaceutical composition. In addition, it is used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions by conventional methods. obtain.

  Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, Examples include calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. When the composition is formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants and the like that are usually used.

  The pharmaceutical composition according to the invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, Determined by the type of disease, severity, activity of the drug, sensitivity to the drug, administration time, route of administration and excretion ratio, duration of treatment, factors including concurrent drugs, and other factors well known in the medical field obtain.

  The pharmaceutical composition according to the present invention may be administered simultaneously, separately or sequentially, preferably single, or sequentially, in order to enhance the therapeutic effect. Multiple doses can be administered. It is important to take into account all of the above factors and to administer an amount that can achieve the maximum effect in a minimum amount without side effects, which can be readily determined by one skilled in the art. Specifically, the effective amount of the pharmaceutical composition according to the present invention depends on the patient's age, sex, condition, weight, absorption of active ingredients in the body, inactivation rate and excretion rate, type of illness, drug used in combination. Can change.

  The pharmaceutical compositions of the invention can be administered to an individual by a variety of routes. All modes of administration can be envisaged, for example, administered by oral administration, intranasal administration, transbronchial administration, arterial injection, intravenous injection, subcutaneous injection, intramuscular injection, or intraperitoneal injection. The daily dose is about 0.0001 mg / kg to 100 mg / kg, preferably 8 mg / kg to 20 mg / kg, and is preferably administered once to several times a day. It is not limited to. When the daily dose of the pharmaceutical composition is maintained at 8 mg / kg to 20 mg / kg, both PPAR-γ (Peroxisome proliferator-activated receptor-gamma) and PPAR-α (Peroxisome proliferator-activated receptor-receptor-activated receptor) Can be activated, and has the advantage that the problems due to toxicity can be minimized.

  The pharmaceutical composition of the present invention is determined by the type of drug that is the active ingredient, as well as various related factors such as the disease being treated, the route of administration, the age, sex, weight, and severity of the disease.

As another aspect of the present invention, the present invention provides a method for treating a metabolic disease comprising the step of administering the pharmaceutical composition to an individual.

  In the present invention, an “individual” means a subject in need of treatment for a disease, and more specifically, a human or non-human primate, mouse, rat, dog, Means mammals such as cats, horses, and cows.

  As a result, this invention provides the prevention or treatment use of the metabolic disease containing the said pharmaceutical composition.

  In the present invention, amodiaquine or a pharmaceutically acceptable salt thereof can be used for a health functional food composition for preventing or ameliorating metabolic diseases.

  The term “amelioration” as used in the present invention means all acts that at least reduce the parameters associated with the condition to be treated, eg the degree of symptoms. At this time, the health functional food composition may be used before or after the onset of the disease, simultaneously with the therapeutic agent or separately for the prevention or improvement of the metabolic disease.

  The term “health functional food composition” used in the present invention includes one or more of carriers, diluents, excipients and additives, and includes tablets, pills, powders, granules, powders, capsules. , And one selected from the group consisting of a liquid dosage form, and preferably a liquid dosage form, but is not limited thereto.

  Examples of foods that can be added to the composition of the present invention include various foods, powders, granules, tablets, capsules, syrups, drinks, gums, teas, vitamin complexes, and health functional foods. Additives further included in the present invention include natural carbohydrates, flavoring agents, nutrients, vitamins, minerals (electrolytes), flavoring agents (synthetic flavoring agents, natural flavoring agents, etc.), coloring agents, fillers, pectinic acid and Selected from the group consisting of its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, antioxidants, glycerin, alcohol, carbonating agents, and pulp One or more components can be used. Examples of the aforementioned natural carbohydrates are monosaccharides such as glucose, fructose, etc .; disaccharides such as maltose, sucrose, etc .; and polysaccharides such as normal sugars such as dextrin, cyclodextrin, and xylitol, sorbitol, erythritol Such as sugar alcohol. As the flavoring agent, natural flavoring agents [thaumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.)] and synthetic flavoring agents (saccharin, aspartam, etc.) can be advantageously used.

  In addition to the above, the composition according to the present invention comprises various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and The salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonates used in carbonated beverages, and the like can be included.

  In addition, the composition according to the invention can contain pulp for the production of natural fruit juices and vegetable drinks. Such components can be used independently or in combination. Specific examples of the carrier, excipient, diluent and additive include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, gum arabic, calcium phosphate, alginate, From the group consisting of gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinyl chloride, cellulose, polyvinyl pyrrolidone, methyl cellulose, water, sugar syrup, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil It is preferred to use one or more selected.

  Hereinafter, preferred examples will be presented to help understanding of the present invention. However, the following examples are provided only for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[Preparation example]
Amodiaquin used in the following examples was purchased from Sigma-Aldrich.

Example 1. Activation measurement of PPAR-γ (Peroxisome proliferator-activated receptor-gamma) or PPAR-α (Peroxisome proliferator-activated receptor-alpha) as an activation measure of PPPAR-γ (Peroxisome proliferator-activated receptor-gamma) Three vectors were used for this purpose. a vector expressing a yeast transcription factor GAL4-DBD (DNA binding domain) and human PPAR-γ-LBD (ligand binding domain) or PPAR-α-LBD (ligand binding domain) in the SV40 promoter of the pZeo vector; A vector in which a gene in which a base sequence (5′-CTCGGAGGACAGTACTCCG-3 ′) to which the GAL4 gene can bind is repeated with a reporter gene luciferase (luciferase) is bound, and beta galactosidase (β -Galactosidase) was used by a known method (Cell, 68: 879-887, 1992).

Activation of luciferase expression was carried out 6 hours after BE (2) C cells were transformed with GAL4-PPAR-γ-LBD plasmid or GAL4-PPAR-α-LBD plasmid and GAL4-luciferase vector, β-galactosidase vector, Cells treated with amodiaquine for 20 hours were grown in a 5% CO ₂ incubator and then measured. At this time, an experimental group in which amodiaquine was treated together at different concentrations (0.01 to 50 μM), a control group in which DMSO (dimethylsulfoxide) 0.3% was treated, and rosiglitazone which is a compound known as a PPAR-γ ligand (Sigma, USA) positive control group treated together by concentration (0.001-50 μM), WY-14, 643 (Sigma, USA), a compound known as PPAR-α ligand, by concentration (0 Chloroquine (7-chloro-4- (4-diethylamino-1-quinoylamino) quinoline) (Sigma, a compound known as an analog of amodiaquine treated together with .01-50 μM) USA) by concentration And compared the treated positive control group together to 0.001~50μM). The experimental results were t-validated between the experimental group and the control group, the significance was verified, and a statistically significant difference was shown.

  As a result, as shown in FIGS. 1a and 1b, the group treated with amodiaquine had a higher PPAR concentration-dependently compared to the positive control group treated with rosiglitazone, a compound known as PPAR-γ ligand. In the positive control group treated with WY-14, 643, a compound known as PPAR-α ligand, and chloroquine, a compound known as an analogue of amodiaquine Activity did not appear. In addition, as shown in FIG. 1c and FIG. 1d, in the same manner as the positive control group treated with WY-14, 643, which is a compound known as a PPAR-α ligand, the group treated with amodiaquine was highly concentration-dependent. The positive control group treated with rosiglitazone, a compound known as a PPAR-γ ligand, and chloroquine, a compound known as an analog of amodiaquine, exhibit PPAR-α activity, but may not have PPAR-α activity. I understood.

  Therefore, it is confirmed that amodiaquine treatment has the effect of promoting both PPAR-γ and PPAR-α activity, and prevention or treatment of amodiaquine against metabolic diseases such as second diabetes, which is a disease associated with PPAR-γ. It can be used for prevention or treatment of metabolic diseases such as obesity, dyslipidemia, cardiovascular disease, fatty liver, etc. regulated by PPAR-α signal.

  Also, from the results of FIG. 1b and FIG. 1d, amodiaquine promotes both PPAR-γ and PPAR-α activity due to the structural features in which the benzene ring and the hydroxyl group are substituted, but as an analog of amodiaquine Was also found to not promote the same activity.

Example 2 Measurement of glucose absorption value (uptake) effect of C2C12 myotube cells In muscle, fat, hepatocytes, etc., insulin receptor phosphorylation occurs due to signal transduction by insulin, and various proteins located in the lower layer are phosphorylated. Then, glucose absorption ability increases and, as a result, blood sugar is lowered. Therefore, in order to confirm whether amodiaquine is effective for diabetes, a glucose absorption ability evaluation experiment was advanced. C2C12 myoblast cells, which are muscle cells, were cultured in DMEM containing 10% BSA (bovine serum albumin). When the cell density reached about 80-90%, it was replaced with a DMEM culture medium containing 2% horse serum, C2C12 myoblast was induced to completely differentiate into myotube, and then experimented. Proceeded. Compounds that are known as positive control groups of 10 and 30 μM concentrations of amodiaquine, DMSO (Dimethyl Sulfoxide) 0.1% and glucose absorption capacity together with DMEM medium containing 0.5% BSA in fully differentiated C2C12 myotube cells Rosiglitazone (Sigma, USA) 50 μM was mixed well and then treated for 24 hours. After treatment for 24 hours, the medium was removed, and the plate was washed with 3 mL of KRP (0.1% BSA + 5 mM glucose) buffer on a plate maintained at 37 ° C. to remove the remaining sample. Washing was repeated three times at 20 minute intervals. Next, 1 mL of KRP buffer was injected, and a solution (0.2 mM, 0.2 μCi) of 2-DOG unlabeled and [ ³ H] 2-DOG (Amersham Pharmacia) in KRP buffer was added at 37 ° C. For exactly 10 minutes. After washing with 3 mL of cold phosphate buffered saline to stop the glucose absorption reaction, the cells were further washed twice with phosphate buffered saline, and the cells were air-dried for about 1 hour, and then 1 mL of 0.1% SDS. In addition, the sample was dissolved while being pushed or pulled with a pipette, 300 μL of the lysate was taken, and the radioactivity was measured with a liquid scintillation counter (Perkin Elmer, USA).

  As a result, as shown in FIG. 2, it was confirmed that the glucose absorption value of the amodiaquine treatment group was further increased as compared with the glucose absorption value of the rosiglitazone treatment group as a positive control group.

  Therefore, from the above results, it was found that amodiaquine has the effect of increasing the activity of PPAR-γ, which is a typical target protein of antidiabetic agent, in the cells and promoting glucose absorption inside the muscle cells.

Example 3 FIG. Measurement of blood glucose-lowering effect and blood glucose-regulating effect in mice with amodiaquin
3-1. 5-week-old KKAy purchased from Amodiaquine and negative control group-administered CELLON BIO INC. Was preliminarily raised for 1 week and then divided into 2 groups of 5 animals each.

  One group was administered phosphate buffered saline as a negative control group, and two groups were orally administered daily for 6 weeks at a concentration of 18 mg / kg amodiaquine.

3-2. Measurement of fasting blood glucose lowering effect and blood glucose regulation effect in mice 6 weeks fasting blood glucose was measured by collecting whole blood from the tail vein at 1, 2, 5, and 6 weeks after fasting for 12 hours. A blood glucose strip (Korea, Gyeonggi-do, Green Cross) was used for blood glucose measurement. The experimental results were t-tested between the experimental group and the control group, the significance was verified, and statistically significant difference was shown (* p <0.05, ** p <0.005). . In addition, in order to confirm the blood glucose control effect, after fasting for 16 hours, 2 g / kg of glucose was injected into the abdominal cavity of the control and experimental group animals, and the blood glucose level was measured at intervals of 30 minutes for 2 hours. For the measurement of blood glucose level, a glucose tolerance test (IPGTT, intraperitoneal glucose tolerance test) was used. The experimental results were subjected to t verification by group of the experimental group and the control group, the significance was verified, and statistically significant differences were shown (* p <0.05, ** p <0. 005).

  As a result, as shown in FIG. 3 a, it was confirmed that fasting blood glucose was significantly reduced in mice ingested amodiaquine compared to the control group. In addition, as shown in FIG. 3b, glucose was administered in the amodiaquine administration group compared with the control group, and it was confirmed that blood glucose decreased rapidly after 2 hours. Specifically, the fasting blood glucose of the control group was 132.4 mg / dL, while the fasting blood glucose of the amodiaquine administration group was 100.2 mg / dL. The blood glucose of amodiaquine was 207 mg / dL, although it was 2 mg / dL.

  Therefore, since amodiaquin has an excellent effect of reducing blood glucose concentration, it can be seen that a pharmaceutical composition containing amodiaquine as an active ingredient can be conveniently used for the prevention or treatment of diabetes and has the effect of reducing fasting blood glucose. Therefore, it was found that it can be usefully used as an agent for preventing or treating insulin-resistant type 2 diabetes.

Example 4 Effect of amodiaquin on glycated hemoglobin (HbA1C) content A part of glucose distributed in blood is firmly bound to erythrocytes, and this is called glycated hemoglobin (HbA1C). For blood glucose control, not only blood glucose levels but also glycated hemoglobin values are always investigated together. This is because 1% reduction in glycated hemoglobin has the effect of reducing complications due to diabetes by 20% or more. In this example, the content of glycated hemoglobin in mice by ingestion of amodiaquine is examined.

4-1. In order to measure glycated hemoglobin in mice by amodiaquine and negative control group-administered amodiaquine, 5-week-old KKAy was purchased from Theron Bio Inc., preliminarily raised for 1 week, and then divided into 2 groups of 5 mice each. As in Example 3 above, the first group of experimental animals were administered phosphate buffered saline and set as a control run group, and the second group was a 1 ml syringe with amodiaquine at a concentration of 18 mg / kg daily for 6 weeks. Orally.

4-2. In order to measure the glycated hemoglobin lowering effect of amodiaquine in mice, whole blood was collected from the tail vein of animals in the control and experimental groups and injected into easy A1c cartridge, then easy A1c analyzer (Seoul, Korea) , Asan Pharmaceutical). The experimental results were subjected to t-validation for each of the experimental group and the control group to verify the significance, and showed a statistically significant difference (** p <0.005).

  As a result, as shown in FIG. 4, it was confirmed that the production of glycated hemoglobin was suppressed by nearly 69% in the amodiaquine-ingested mice as compared to the control group mice.

  Therefore, it was found that amodiaquine has the effect of reducing glycated hemoglobin.

Example 5 FIG. Measurement of weight loss with amodiaquin
5-1. Experimental Animal Design and Experimental Diet Composition To measure mouse weight loss due to amodiaquine, 7-week-old C57BL / 6 male mice (Charles River Laboratories, Tokyo, Japan) were purchased under certain conditions (temperature: 22 ±). 2 ° C., relative humidity: 55 ± 10%, one cycle: 12 hours). Seven animals were grouped and water and food were freely supplied in cages and purified for one week before the experiment and used for the experiment.

  After the acclimatization period was over, it was divided into 7 groups and the administration of diet, amodiaquine and positive control group (WY-14, 643, rosiglitazone) was advanced during the period as shown in Table 1 below.

LFD (10% kcal as fat; D12450B, Research Diets Inc.)
HFD (60% kcal as fat; D12492, Research Diets Inc.)

5-2. Measurement of body weight change in mice The body weight change survey was conducted for mice fed normal diet, high fat diet-induced obese mice fed high fat, and amodiaquine and positive control group for high fat (WY-14,643 and rosiglitazone) High fat diet-induced obese mice that were administered the weight were measured using an electronic balance (Dragon 204 / S, Mettler Toledo, USA) for 21 weeks once a week at 10:00 am. The body weight average was obtained by adding the body weights of 7 mice per group and dividing the mice into the average body weight. The above experimental results show that a t-test is performed for each group between a high fat diet-induced obesity control group, amodiaquine and a positive control group (WY-14,643 and rosiglitazone), its significance is verified, statistical (* P <0.05, ** P <0.005, *** P <0.0005).

  As a result of the experiment, as shown in FIG. 5a, it can be observed that the body weight of the high-fat diet-induced obese mice in the amodiaquine administration group is significantly decreased than the body weight of the high-fat-induced obese mice. , 643) can be observed. In the case of FIG. 5c in which amodiaquine was administered after inducing obesity with high fat, it could be observed that the body weight of the obese mice induced with high fat diet was significantly reduced. On the other hand, in the case of the positive control group (rosiglitazone) which is an agent of PPAR-γ, it was confirmed that it was similar to the high-fat diet-induced obese mice or that the body weight was further increased. .

5-3. Dietary intake measurement of high-fat diet-induced obese mice Dietary intake studies were conducted on mice grown on normal diet, high-fat diet-induced obese mice fed high fat, and high fat amodiaquine and positive controls The intake of high fat diet-induced obese mice administered with the group (WY-14,643 and rosiglitazone) was measured daily at 11:00 am as a reference. Since the average of food intake was 7 per group, the average food intake was divided into 7 for each group. Daily intake was shown in terms of kcal. As a result of the experiment, as shown in FIGS. 5b and 5d, food intake and high fat diet-induced obesity in high fat diet-induced obese mice administered with amodiaquine and a positive control group (WY-14,643 and rosiglitazone) It could be observed that there was no difference between the food intake of the mice.

  The results show that amodiaquine has the effect of reducing the body weight of mice regardless of food intake, and therefore, it can be used as an anti-obesity pharmaceutical.

Example 6 Measurement of heat production effect by amodiaquin Adipocytes are classified into white adipocytes that act on fat accumulation and brown adipocytes that act on heat production, although in a very small amount. Brown adipocytes have a diet-induced heat production effect that warms the body after a meal, and when the temperature is lowered, activity increases, heat is produced, and body temperature is maintained. Ob / ob mice, which are hereditary obese animals that are experimental models of obesity, have poor functioning of brown adipocytes, and when exposed to a low temperature of 4 ° C., the body temperature gradually falls and die after about 4 hours. . If the function of brown adipocytes is not exerted accurately, there is little energy lost by heat at daily temperatures, so there is a high possibility that excess energy will accumulate and obesity will occur. Therefore, in this example, the heat production capacity of high fat diet-induced obese mice by amodiaquine administration is examined.

6-1. Measurement of heat production capacity of high fat diet-induced obese mice A 4 ° C. cold test was performed in order to measure heat production capacity of mice subjected to high fat diet for 14 weeks among the experimental animals designed in Example 5. (Spiegelman B.M. et al, Cell 92: 829-839, 1998). Hereinafter, the measurement method will be described in detail. Before exposing the mice of the high fat diet-induced obese mouse group to 4 ° C., the body temperature was measured and recorded as the experimental start measurement temperature, exposed to a 4 ° C. room for up to 6 hours, and the body temperature was measured every hour. Body temperature was measured using a mouse rectal thermometer (testo 925, Germany). The thermal production measurement value indicates the temperature measured every hour. The experimental results were subjected to t-test for each group of the experimental group and the control group, the significance was verified, and statistically significant difference was shown (* p <0.05, *** p <0). .0005).

  As a result of the experiment, as shown in FIG. 5, it was confirmed that the amodiaquine-administered group high-fat obesity-induced mice had less decrease in body temperature than the high-fat obesity-induced mice, and was found to have excellent heat production effects.

  Therefore, from the above results, it was found that amodiaquine according to the present invention increases the heat production activity of high fat diet-induced obese mice and has the effect of reducing the possibility of becoming obese because much energy is produced as heat. .

Example 7 Measurement of blood glucose control effect in mice using amodiaquine In this example, a glucose tolerance test and an insulin resistance test were performed in order to measure the blood glucose control effect of the experimental animals designed in Example 5.

7-1. The mice were fasted for 16 hours after the oral measurement of the test , and then 2 g / kg of glucose was orally administered to the animals of the control group and the experimental group, and the blood glucose level was measured at 30-minute intervals for 2 hours. For the measurement of blood glucose level, a glucose tolerance test (OGTT, oral glucose tolerance test) was used. The experimental results were obtained by performing a t-test for each group between a high-fat diet-induced obese mouse control group, amodiaquine, a positive control group (WY-14, 643), and a normal diet-fed mouse, and verified its significance. Statistically significant differences were shown (* p <0.05, ** p <0.005, *** p <0.0005).

  As a result, as shown in FIG. 7a, glucose was administered in the amodiaquine administration group as compared with the high fat diet-induced obese mouse control group, and after 2 hours, it was confirmed that blood glucose decreased rapidly. Specifically, after 2 hours of glucose loading in the high fat diet-induced obese mouse control group, the blood glucose was 180.5 mg / dL, whereas the blood glucose of amodiaquine was 139.1 mg / dL.

  Therefore, since amodiaquin has an excellent effect of reducing blood glucose concentration, it has been found that a pharmaceutical composition containing amodiaquine as an active ingredient can be conveniently used for an insulin resistant type 2 diabetes preventive and therapeutic agent. It was.

7-2. After the mice were fasted for 16 hours after insulin resistance test measurement , 0.5 U / kg insulin was administered into the abdominal cavity of the animals in the control group and experimental group, and the blood glucose level was measured at 30-minute intervals for 2 hours. For the measurement of blood glucose level, an insulin tolerance test (IPITT, intraperitoneal insulin tolerance test) was used. The results of the experiment were as follows: t-test was conducted for each group among the high-fat diet-induced obese mouse control group, amodiaquine, positive control group (WY-14,643 and rosiglitazone) and normal diet-fed mice. Tested and showed statistically significant differences (* p <0.05, ** p <0.005, *** p <0.0005).

  As a result, as shown in FIG. 7b, insulin was administered in the control group and the experimental group of high fat diet-induced obese mice, and the insulin resistance was measured. As a result, the blood glucose level was the lowest in 30 minutes in all groups. And then gradually increased. In the high-fat diet-induced obese mouse control group, blood glucose increased to fasting blood glucose at 120 minutes. In normal feed intake group, positive control group (WY-14, 643), and amodiaquine administration group, blood glucose was 2 hours later. However, blood sugar was maintained at a level lower than fasting blood sugar. Moreover, insulin was administered to the obese mouse control group and the experimental group in which insulin resistance induced by high fat induction in FIG. As a result of measuring the insulin resistance, the high-fat diet-induced obese mice and the amodiaquine administration group showed the lowest value in 30 minutes and then gradually increased. In the positive control group (rosiglitazone) and the normal feed intake group, blood glucose showed a minimum value at 60 minutes, and then gradually increased. In the high-fat diet-induced obese mouse control group, blood glucose rose to nearly 70% of the initial blood glucose at 120 minutes, and in the normal feed intake group, positive control group (rosiglitazone), and amodiaquine administration group, blood glucose was 2 hours later. However, the blood sugar level was maintained at about 40 to 45% of the initial blood sugar level.

  Accordingly, it has been found that the intake of amodiaquine has an effect of increasing insulin sensitivity, and thus can be usefully used as an agent for preventing or treating insulin-resistant type 2 diabetes.

Example 8 FIG. Measurement of fatty liver preventive effect by amodiaquine Except for alcoholic fatty liver caused by excessive intake of alcohol, the causes of fatty liver include nutritional imbalances related to high calorie, high fat diet and simple sugar intake. It is done. In particular, continuous intake of a high calorie or high fat diet leads to impaired lipid metabolism between fat synthesis and degradation in the liver and induces fatty liver (Fromment B. et al., Mitochondrion 6: 1-28, 2006).

  Thus, in this example, the effect of amodiaquine treatment on induction of fatty liver was examined.

8-1. Tissue collection of high-fat diet-induced obese mouse group Of the experimental animals designed in Example 5, the mice of the high-fat diet-induced obese mouse group fed with high fat for 14 weeks were sacrificed by cervical deboning and then dissected. The abdomen was incised with a scalpel, and the liver was removed. The extracted liver tissue was fixed in a 10% formalin solution in order to prevent contraction. The fixed tissue is washed with flowing water after 24 hours, and then the general tissue dehydration, transparency and permeation process is processed for 14 hours using an automatic tissue processing device (6460B, Sakura, Japan) equipment, An automatic embedding device (Tissue-Tex, Japan) was used for the production and cooling of the paraffin block. Using the rotary microtome (Rotary Microtome 2040, Japan), the produced paraffin block was continuously sliced in a thickness of 4 to 5 μm in a vertical direction, and attached to the slide through a floating hot water bath and a stretcher process.

8-2. Observation of fatty liver prevention effect by amodiaquine After slicing a sliced tissue section with hematoxylin, the overstained part was washed with flowing tap water and then immersed in 1% HCl, 70% A / C solution 3-5 times By doing so, the nucleus was bluened. Next, the water is washed thoroughly for about 5 to 10 minutes and stained with a cytoplasmic control stain so that the nucleus has a clear color, and then the excess eosin solution is washed with flowing water for 15 seconds, dehydrated and cleared. Went through the process. Each liver tissue was observed using an optical microscope (BX50, Olympus, Japan), and each group of tissues was photographed with a CCD camera (PM-C35DX, Olympus, Japan) attached to the microscope.

  As a result of the experiment, as shown in FIG. 8, the liver of the high fat diet-induced obese mouse is completely filled with fat, whereas in the case of the liver of the high fat diet-induced obese mouse treated with amodiaquine, The same morphology as that of normal mouse liver was confirmed.

  Therefore, from the above results, it was found that amodiaquine according to the present invention is excellent in the effect of inhibiting fatty liver.

Example 9 Confirmation of target gene expression by activation of PPAR-α in liver, muscle, and adipose tissue by administration of amodiaquin PPAR-α is an ACOX (acyl-CoA oxidase) gene that is an enzyme involved in fatty acid oxidative metabolism pathway ), CPT-1 (carnitine palmitol transferase-1), and mCAD (medium chain acyl-CoA dehydrogenase), and is known to reduce fatty acid synthesis (Dreyer Christine. Cell, 68: 879-887, 1992). Therefore, when the expression levels of the ACOX, CPT-1 and mCAD genes are measured, the oxidation efficacy of fatty acids can be grasped. Thus, in this example, the effect of administration of amodiaquine on liver, muscle, and adipose tissue on the expression levels of ACOX, CPT-1 and mCAD genes was examined.

  Each tissue was sacrificed by the cervical deboning method of the high-fat diet-induced obese mouse group that was fed high fat for 14 weeks among the experimental animals designed in Example 5, and then fixed to the dissecting fixation frame. An incision was made with a scalpel and the liver, muscle, and adipose tissue were removed and used. The primer base sequences of β-actin, ACOX, CPT-1 and mCAD are as follows.

β-actin forward: 5′-GGG AAG GTG ACA GCA TTG-3 ′
reverse: 5′-ATG AAG TAT TAA GGC GGA AGA TT-3 ′
ACOX forward: 5′-ACA CTA ACA TAT CAA CAA GAG GAG-3 ′
reverse: 5'-CAT TGC CAG GAA GAC CAG-3 '
CPT-1 forward: 5′-CCA CCT CTT CTG CCT CTA T-3 ′
reverse: 5′-TTC TCA AAG TCA AAC AGT TCC A-3 ′
mCAD forward: 5′-CCG AAG AGT TGG CGT ATG-3 ′
reverse: 5′-AGC AAG AAT CAC AGG CAT T-3 ′

After each tissue was polished using a pulverizer, RNA was extracted using Trizol, and cDNA was synthesized using reverse transcriptase polymerase chain reaction (RT PCR).
As a control group, β-actin was used, and each primer was used in order to examine the expression level of the ACOX, CPT-1 and mCAD genes involved in the degradation of the target gene and fatty acid by the activation of PPAR-α. Real-time polymerase chain reaction (RT PCR, Real-time polymerase chain reaction) was performed. (95 ° C for 3 minutes, <95 ° C for 10 seconds, 60 ° C for 10 seconds, 72 ° C for 30 seconds> 39 times, 95 ° C for 10 seconds, 65 ° C for 5 seconds). ACOX, CPT-1 and mCAD were corrected with β-actin, and the result values were calculated. The above experimental results show that a t-test was performed for each group between the high fat diet-induced obese mouse control group and amodiaquine and positive control group (WY-14, 643) mice, the significance was verified, and statistically significant (* P <0.05, ** p <0.005, *** p <0.0005).

  As a result, as shown in FIG. 9a, FIG. 9b, and FIG. 9c, it was confirmed that the gene expression level increased by about 2 to 15 times or more in the experimental group administered with amodiaquine compared to the control group.

  Therefore, the treatment of amodiaquine is a target gene due to the activation of PPAR-α, and in view of increasing the expression of ACOX, CPT-1 and mCAD genes involved in fatty acid degradation in each tissue, amodiaquine is a PPAR-α. Is activated, and the expression of the target gene of PPAR-α can be regulated, and it was determined that fat accumulation can be suppressed by promoting the oxidation of fatty acids.

Example 10 Confirmation of target gene expression by anti-inflammatory reaction in adipose tissue by administration of amodiaquine Adipocytes are differentiated from hepatic lobe cells (predipocyte) and lipid metabolism function, sugar metabolism function, This in turn leads to changes in adipocytokine secretion (Cristina M. Rondine, Endocrine, 29: 81-90, 2006). TNFα, MCP-1 and iNOS that are increasing in obese patients promote fat differentiation through the development of adipocyte inflammation and increase the prevalence of other adult diseases (Tomasz J. Guzik et al., J Physiol Pharmacol). 57: 505-528, 2006). TNF-α is a cell secretory substance that plays an important role in the inflammatory response, and MCP-1 is an inflammatory chemokine that is secreted by adipocytes and affects obesity, insulin resistance, and arteriosclerosis It is known. In addition, iNOS is an inflammatory precursor and is known to promote an inflammatory reaction.

  Therefore, by measuring the expression levels of the TNFα, MCP-1 and iNOS genes, the anti-inflammatory efficacy can be grasped. Thus, in this example, the effect of amodiaquine administration on the expression levels of TNFα, MCP-1 and iNOS genes in adipose tissue was examined.

  Each tissue was sacrificed by the cervical deboning method of the high-fat diet-induced obese mouse group that was fed high fat for 14 weeks among the experimental animals designed in Example 5, and then fixed to the dissecting fixation frame. An incision was made with a scalpel and the adipose tissue was excised and used. The primer base sequences of β-actin, TNFα, MCP-1 and iNOS are as follows.

β-actin forward: 5′-GGG AAG GTG ACA GCA TTG-3 ′
reverse: 5′-ATG AAG TAT TAA GGC GGA AGA TT-3 ′
TNFα forward: 5′-ATG AGA AGT TCC CAA ATG GC-3 ′
reverse: 5′-TTT GAG AAG ATG ATC ATC TGA GTG TGA G-3 ′
MCP-1 forward: 5′-AAT GAG TAG GCT GGA GAG-3 ′
reverse: 5′-TCT CTT GAG CTT GGT GAC-3 ′
iNOS forward: 5′-GCT TCT GGC ACT GAG TAA-3 ′
reverse: 5′-GGA GGA GAG GAG AGA GAT-3 ′

After adipose tissue was pulverized using a pulverizer, RNA was extracted using Trizol, and cDNA was synthesized using reverse transcriptase polymerase chain reaction (RT PCR).
As a control group, β-actin was used, and in order to examine the expression levels of TNFα, MCP-1 and iNOS genes involved in inflammatory reaction, real-time polymerase chain reaction (RT PCR, Real -Time polymerase chain reaction). (95 ° C for 3 minutes, <95 ° C for 10 seconds, 60 ° C for 10 seconds, 72 ° C for 30 seconds> 39 times, 95 ° C for 10 seconds, 65 ° C for 5 seconds). TNFα, MCP-1 and iNOS were corrected with β-actin, and the result values were calculated. The above experimental results show that a t-test was performed for each group between the high fat diet-induced obese mouse control group and amodiaquine and positive control group (WY-14, 643) mice, the significance was verified, and statistically significant (* P <0.05, ** p <0.005).

  As a result, as shown in FIG. 10, it was confirmed that the gene expression level decreased in the experimental group administered with amodiaquine by almost 5 to 40% compared to the control group.

  Therefore, in view of suppressing the expression of TNFα, MCP-1 and iNOS genes involved in the treatment of amodiaquine in the anti-inflammatory reaction in each tissue, by suppressing the factors that amodiaquine has an important effect on the inflammatory reaction, It was determined to affect obesity, insulin resistance, and arteriosclerosis.

  The above description of the present invention is given for the purpose of illustration, and those having ordinary knowledge in the technical field to which the present invention pertains can be used without changing the technical idea and essential features of the present invention. It can be understood that it can be easily modified in a typical form. Accordingly, it should be understood that the embodiments described above are illustrative in all respects and are not limiting.

Claims (11)

Amodiaquin represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, PPAR-γ (Peroxisome proliferator-activated receptor-gamma) and PPAR-α (Peroxisome proliferator-- A pharmaceutical composition for preventing or treating metabolic diseases, characterized by activating both receptor-alpha).
  The composition according to claim 1, wherein the daily dose of the composition is 8 mg / kg to 20 mg / kg.   The metabolic diseases include diabetes, hyperglycemia, impaired glucose tolerance, obesity, dyslipidemia, arteriosclerosis, hypertension, insulin resistance syndrome, and fat resistance syndrome. The composition according to claim 1, wherein the composition is one or more selected from the group consisting of liver, cardiovascular disease, and syndrome X.   The dyslipidemia is one or more selected from the group consisting of hyperlipidemia, hypertriglyceremia, and hypercholesteremia, wherein the dyslipidemia is hyperlipidemia, hypertriglyceremia, or hypercholesteremia. Item 4. The composition according to Item 3.   The composition according to claim 1, wherein the metabolic disease is type 2 diabetes that responds to activation of PPAR-γ.   The metabolic disease is one selected from the group consisting of obesity, dyslipidemia, cardiovascular disease, and fatty liver that occurs as a side effect when PPAR-γ is activated in response to PPAR-α activation It is the above, The composition of Claim 1 characterized by the above-mentioned. It contains amodiaquin or a pharmaceutically acceptable salt thereof represented by the following chemical formula 2 as an active ingredient, and PAR-γ (Peroxisome proliferator-activated receptor-gamma) and PPAR-α (Peroxisome proliferator--). A functional food composition for preventing or ameliorating metabolic diseases, characterized by activating both receptor-alpha).
  The metabolic diseases include diabetes, hyperglycemia, impaired glucose tolerance, obesity, dyslipidemia, arteriosclerosis, hypertension, insulin resistance syndrome, and fat resistance syndrome. 8. The composition according to claim 7, wherein the composition is one or more selected from the group consisting of liver, cardiovascular disease, and syndrome X.   The dyslipidemia is one or more selected from the group consisting of hyperlipidemia, hypertriglyceremia, and hypercholesteremia, wherein the dyslipidemia is hyperlipidemia, hypertriglyceremia, or hypercholesteremia. Item 9. The composition according to Item 8.   8. The composition of claim 7, wherein the metabolic disease is type 2 diabetes that responds to PPAR-γ activation.   The metabolic disease is one selected from the group consisting of obesity, dyslipidemia, cardiovascular disease, and fatty liver that occurs as a side effect when PPAR-γ is activated in response to PPAR-α activation It is the above, The composition of Claim 7 characterized by the above-mentioned.